This invention relates to a topical ophthalmic formulation comprising a cyclosporin.
Cyclosporins represent a class of nonpolar cyclic oligopeptides having numerous pharmacological properties.
They are more particularly known for their immunosuppressive and antiinflammatory activity, and have also been described as being effective in enhancing or reestablishing tear secretion by the lachrymal gland in patients suffering from immune-mediated keratoconjunctivitis sicca.
Cyclosporins of natural origin which in their majority comprise cyclosporin A and in their minority the cyclosporins B to I can be obtained from the fungus Trichoderma polysporum. 
Like a large number of their analogs and isomers, cyclosporins can also be obtained by synthesis.
The cyclosporin most widely studied and used in pharmacy among the cyclosporins is cyclosporin A.
The activity of a cyclosporin and particularly of cyclosporin A in enhancing or reestablishing tear secretion by the lachrymal gland could be improved by improving absorption of cyclosporin in the lachrymal gland.
For reasons of the very low solubility of cyclosporins in water (20 to 30 xcexcg/mL for cyclosporin A), it has been very difficult to prepare an ophthalmic composition containing a cyclosporin dissolved in an aqueous medium.
It is for this reason that the cyclosporins, known to be lipophilic, have mainly been used in oil-based formulations.
U.S. Pat. No. 4,839,342 describes a topical ophthalmic composition containing a cyclosporin, particularly cyclosporin A, and an excipient, to increase tear production in patients suffering from a lack of tears in the eyes because of a dysfunction of the lachrymal glands. The excipients specifically described are olive oil, peanut oil, castor oil, polyethoxylated castor oil, mineral oils, vaselines, dimethyl sulfoxide, an alcohol, liposomes, silicone oils or their mixtures.
FR-A-2,638,089 describes a topical ophthalmic composition which contains a cyclosporin as the active substance and a vegetable oil such as olive oil, peanut oil, castor oil, sesame oil and maize germ oil as the vehicle, as well as vaseline, to treat illnesses and immunological or inflammatory conditions affecting the eye, and particularly keratoconjunctivitis sicca (KCS) or dry eyes.
However, the oil-based topical ophthalmic formulations have disadvantages such as a disagreeable feeling in the eyes, or lead to dim-sightedness. The oils may moreover reinforce the dry-eye symptoms.
Oil-based topical ophthalmic formulations containing cyclosporin also are physically unstable, because the cyclosporins tend to undergo conformational changes and to precipitate.
These formulations moreover have a poor bioavailability and low eye tolerance, which shows by an irritation of the eyes.
For the purposes of minimizing certain of the above disadvantages such as discomfort in use, and of improving the bioavailability and tolerability of the formulation, it has been proposed in WO 95/31211 to reduce the amount of oil and disperse the oil phase in water so as to form an emulsion, which gave a topical ophthalmic formulation in the form of an emulsion based on water and on oil comprising a cyclosporin mixed with a triglyceride containing long-chain fatty acids such as castor oil and polysorbate 80. This formulation also contains an emulsifier, for instance Pemulen(copyright).
For the purposes of eliminating the problems of cyclosporin precipitation while improving the bioavailability and tolerability of the formulation, an aqueous topical ophthalmic formulation has been proposed in U.S. Pat. No. 5,951,971 which is free of oil and comprises a cyclosporin in a concentration of 0.01 to 0.075% (w/v), water, and a surfactant in an amount of 0.1 to 3% (w/v) intended to improve the solubility of the cyclosporin in water and selected among the polyethoxylated fatty acid esters, the polyethoxylated alkylphenyl ethers, the polyethoxylated alkyl ethers and their mixtures. According to U.S. Pat. No. 5,951,971, it has been found that polysorbate 80, also known as Tween 80, is inappropriate as a surfactant, because it lacks an activity sufficiently high to solubilize a cyclosporin in the desired concentrations in water.
It is the aim of the present invention to eliminate the above disadvantages and particularly the problems of physical stability, and above all to improve the bioavailability of the formulation in the conjunctiva, cornea, and lachrymal gland as well as the eye tolerance of the formulation, by providing a water-based topical ophthalmic formulation containing a cyclosporin.
This aim was achieved when the inventors had found that the presence of hyaluronic acid and of polysorbate 80 in an aqueous ophthalmic formulation containing cyclosporin surprisingly permitted to solubilize the cyclosporin while improving the bioavailability of the formulation in the conjunctiva, cornea, and lachrymal gland and eye tolerance of the formulation when this formulation is administered topically in the eyes.
Hyaluronic acid is a mucopolysaccharide of biological origin widely distributed in nature. It is present in particular in different animal tissues such as the umbilical cords, the synovial fluid, the vitreous body, the cockscombs and various conjunctive tissues such as the skin and the cartilage.
Chemically speaking, hyaluronic acid is a glycosaminoglycan and composed of alternating, repeating groups of D-glucuronic acid and N-acetyl-D-glucosamine forming a linear chain having a molecular weight as high as 13xc3x97106 daltons.
The pharmaceutical use of hyaluronic acid or one of its salts, and particularly of sodium hyaluronate, has been widely described in the literature. Since hyaluronic acid or its salts are nonimmunogenic substances and have hydrophilic and viscoelastic properties, they have been used for a number of years as substitute for the eye""s vitreous fluid or as a supporting medium in eye surgery, as described for example in U.S. Pat. No. 4,141,973.
Other applications of hyaluronic acid in ophthalmology have also been described.
Thus, EP-A-0,698,388 describes an aqueous ophthalmic composition comprising a salt of hyaluronic acid at a concentration of 0.05 to 2% as an agent increasing the viscosity, to be used as artificial tears.
WO-A-89/017772 describes an oil-based topical ophthalmic composition containing a cyclosporin, intended to enhance or reestablish tear secretion by the lachrymal gland. Hyaluronic acid is cited in a list of products that can be incorporated into the formulation as additives or additional active agents.
According to a first aspect, the subject of the present invention is a water-based topical ophthalmic formulation comprising a cyclosporin, hyaluronic acid or one of its salts, and polysorbate 80.
According to a second aspect, the subject of the present invention is the use of a cyclosporin in association with hyaluronic acid or one of its salts and with polysorbate 80 in preparing a water-based formulation intended for a topical ophthalmic utilization.
The present invention thus provides an ophthalmic formulation in the form of an aqueous solution in which the cyclosporin is solubilized in a micellar form, a formulation which is stable and has a good bioavailability in the conjunctiva, the cornea, the lachrymal gland and the aqueous humor as well as an eye tolerance considerably improved over those in a formulation where the cyclosporin is solubilized in a water-oil emulsion.
Other advantages of the present invention will become apparent from the following detailed description of the invention.
In the present application, the term xe2x80x9ccyclosporinxe2x80x9d is to be understood to include whatever individual member of the class of cyclosporins and their mixtures, unless a particular cyclosporin is specified.
It must also be noted that in the present application, the term xe2x80x9chyaluronic acidxe2x80x9d indifferently means the hyaluronic acid in its acid form or in the form of one of its salts.
In conformity with the present invention, the formulation of the present invention contains a cyclosporin, hyaluronic acid or one of its salts, and polysorbate 80.
The formulation according to the present invention preferably comprises 0.02 to 2% by weight of cyclosporin, 0.01 to 2% by weight of hyaluronic acid or one of its salts, and 0.5 to 40% by weight of polysorbate 80, based on the formulation""s total weight.
The cyclosporins that may be contained in the formulation of the present invention can be of natural or synthetic origin.
According to a preferred embodiment, the cyclosporin contained in the formulation is a cyclosporin A.
One cyclosporin A that can be used to prepare the formulation of the present invention is for instance a commercial cyclosporin A furnished by SIGMA in Switzerland.
The hyaluronic acid contained in the formulation can be, either in its acid form or in the form of one of its salts such as an alkali metal or alkaline-earth metal hyaluronate, for instance sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate or others.
The hyaluronic acid or its salt preferably have a weight-average molecular weight that is not below 1,000,000 daltons, more preferably a weight-average molecular weight in the region of 1,300,000 to 3,000,000 daltons. The molecular weight is preferably about 1,700,000 daltons.
Preferably the hyaluronic acid is in the form of sodium hyaluronate.
Polysorbate 80, also known as Tween 80, is a polyethoxylated sorbitan monooleate known for its uses as a surfactant.
A polysorbate 80 that can be used to prepare the formulation of the present invention is for instance a commercial polysorbate 80 furnished for instance by SIGMA.
In a particularly preferred embodiment, the composition comprises 0.2% by weight of cyclosporin A, 0.1% by weight of hyaluronic acid and 5% by weight of polysorbate 80, based on the formulation""s total weight.
The formulation of the present invention can moreover contain additives such as sorbitol, which is used as an isosmotic agent. Sorbitol has the advantage of having a hydrodynamic volume larger than that of NaCl for instance. Other possible additives are mannitol, polyalcohols and the chlorides of sodium and potassium.
For the formulation of the present invention to be physiologically acceptable, it should preferably have a pH in the range from 6.5 to 7.5 and an osmolality in the range from 290 to 310 mosm/L, preferably 300 mosm/L.
The formulation of the present invention can be packaged as single doses.
The topical formulation of the present invention is administered into the eye in the form of drops, and is useful for enhancing or reestablishing the secretion of tears by the lachrymal gland, and also for stimulating or reestablishing the activity of the lachrymal gland, particularly in patients suffering from keratoconjunctivitis sicca, dry-eye syndrome, Sjxc3x6gren syndrome, chronic vernal keratoconjunctivitis, and as post-operative prophylactic in keratoplasty.
The following examples are intended to illustrate the present invention and its advantages. They must in no case be considered as limiting the scope of the present invention.